Hepatitis: Berasain C

Berasain C, Castillo J, Perugorria MJ, Latasa MU, Prieto J, Avila MA. · Division of Hepatology and Gene Therapy, CIMA-Universidad de Navarra, Pamplona, Spain. · Ann N Y Acad Sci. · Pubmed #19250206 No free full text.

Abstract: A connection between inflammation and cancer has been long suspected. Epidemiological studies have established that many tumors occur in association with chronic infectious diseases, and it is also known that persistent inflammation in the absence of infections increases the risk and accelerates the development of cancer. One clear example of inflammation-related cancer is hepatocellular carcinoma (HCC). HCC is a type tumor that slowly unfolds on a background of chronic inflammation mainly triggered by exposure to infectious agents (hepatotropic viruses) or to toxic compounds (ethanol). The molecular links that connect inflammation and cancer are not completely known, but evidences gathered over the past few years are beginning to define the precise mechanisms. In this article we review the most compelling evidences on the role of transcription factors such as NF-kappaB and STAT3, cytokines like IL-6 and IL-1alpha, ligands of the EGF receptor and other inflammatory mediators in cancer development, with special emphasis in HCC. The molecular dissection of the pathways connecting the inflammatory reaction and neoplasia will pave the way for better therapies to treat cancers.

Berasain C, Castillo J, Prieto J, Avila MA. · Division of Hepatology and Gene Therapy, CIMA, Universidad de Navarra, Pamplona, Spain. · Liver Int. · Pubmed #17311611 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths. This malignancy is often diagnosed at an advanced state, when most potentially curative therapies are of limited efficacy. In addition, HCC is a type of tumor highly resistant to available chemotherapeutic agents, which leaves HCC patients with no effective therapeutic options and a poor prognosis. From a molecular perspective, HCC is a heterogeneous type of tumor. However, in most cases, HCC emerges on a background of persistent liver injury, inflammation and hepatocellular proliferation, which is characteristic of chronic hepatitis and cirrhosis. Recent studies have revealed that dysregulation of a limited number of growth and survival-related pathways can play a key role in HCC development. The epidermal growth factor receptor (ErbB1) can be bound and activated by a broad family of ligands, and can also engage in extensive cross talk with other signaling pathways. This system is considered as an important defense mechanism for the liver during acute tissue injury; however, accumulating evidences suggest that its chronic stimulation can participate in the neoplastic conversion of the liver. Agents that target the ErbB1 receptor have shown antineoplastic activity in other types of tumors, but their efficacy either alone or in combination with other compounds has just started to be tested in experimental and human HCC. Here, we review the evidences that support the involvement of the ErbB1 in HCC development and that provide a rationale for ErbB1 targeting in HCC prevention and treatment.

Guitart A, Riezu-Boj JI, Elizalde E, Larrea E, Berasain C, Aldabe R, Civeira MP, Prieto J. · Division of Hepatology and Gene Therapy, Clinica Universitaria and School of Medicine, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. · J Gen Virol. · Pubmed #16227229 links to  free full text

Abstract: Systems for in vitro culture of Hepatitis C virus (HCV) are essential tools to analyse virus-cell interactions and to investigate relevant pathophysiological aspects of HCV infection. Although the HCV replicon methodology has increased our understanding of HCV biology, this system does not reproduce the natural infection. Recently, tupaia (Tupaia belangeri chinensis) hepatocytes have been utilized for in vitro culture of HCV. In the present work, primary tupaia hepatocytes infected in vitro with HCV were used to analyse the evolution of HCV quasispecies in infected cells and the ability of the virus to influence antiviral and proinflammatory responses in cells sustaining virus replication. The results confirmed the potential of tupaia hepatocytes as a model for HCV infection, although this system is limited by rapid loss of differentiated cell phenotype in culture. These findings revealed an extraordinary plasticity of HCV quasispecies, which underwent rapid evolution to tupaia-tropic variants as early as 24 h after infection. It was also shown that HCV could activate interferon-sensitive genes, albeit modestly in comparison with other viruses such as Semliki Forest virus. Importantly, HCV activated NF-kappaB in primary hepatocytes and upregulated NF-kappaB-responsive genes including the chemokines MCP-1 and CXCL2 (MIP-2). This effect may play a role in induction of the hepatic inflammatory reaction in vivo. In summary, HCV quasispecies adapt rapidly to the specific biology of the host and HCV stimulates a blunted interferon response while inducing a proinflammatory phenotype in the infected cell.

Berasain C, Herrero JI, García-Trevijano ER, Avila MA, Esteban JI, Mato JM, Prieto J. · Division of Hepatology and Gene Therapy, Department of Medicine, Clínica Universitaria, University of Navarra, Pamplona, Spain. · Hepatology. · Pubmed #12829997 No free full text.

Abstract: The Wilms' tumor suppressor WT1 is a transcriptional regulator present in the fetal but not in the mature liver. Its expression and functional role in liver diseases remains unexplored. In this study, we analyzed WT1 expression by reverse-transcription polymerase chain reaction (RT-PCR) and by immunohistochemistry in normal and diseased livers. In addition, we performed in vitro studies in isolated rat hepatocytes to investigate WT1 regulation and function. We detected WT1 messenger RNA (mRNA) in 18% of normal livers, 17% of chronic hepatitis with minimal fibrosis, 49% of chronic hepatitis with bridging fibrosis, and 71% of cirrhotic livers. In cirrhosis, WT1 immunoreactivity was localized to the nucleus of hepatocytes. WT1 mRNA abundance correlated inversely with prothrombin time (P =.04) and directly with serum bilirubin (P =.002) and with the MELD score (P =.001) of disease severity. In rats, WT1 expression was present in fetal hepatocytes and in the cirrhotic liver but not in normal hepatic tissue. In vitro studies showed that isolated primary hepatocytes express WT1 when stimulated with transforming growth factor beta (TGF-beta) or when the cells undergo dedifferentiation in culture. Moreover, we found that WT1 down-regulates hepatocyte nuclear factor 4 (HNF-4), a factor that is essential to maintain liver function and metabolic regulation in the mature organ. Hepatic expression of HNF-4 was impaired in advanced human cirrhosis and negatively correlated with WT1 mRNA levels (P =.001). In conclusion, we show that WT1 is induced by TGF-beta and down-regulates HNF-4 in liver cells. WT1 is reexpressed in the cirrhotic liver in relation to disease progression and may play a role in the development of hepatic insufficiency in cirrhosis.

Berasain C, Betés M, Panizo A, Ruiz J, Herrero JI, Civeira MP, Prieto J. · Department of Medicine and Liver Unit, Medical School and Clínica Universitaria, University of Navarra, Pamplona, Spain. · Gut. · Pubmed #10940283 links to  free full text

Abstract: BACKGROUND: The histopathological spectrum and role of hepatitis viruses in cases of hypertransaminasaemia of unknown aetiology have not been correctly analysed in a sufficiently large number of patients. METHODS: We studied 1075 consecutive patients referred for liver biopsy because of elevation of alanine aminotransferase (ALT) levels for more than six months. From this population we selected those cases in whom the aetiology could not be defined from clinical, biochemical, and serological data obtained before biopsy. In these patients liver biopsies were reviewed, and hepatitis B virus (HBV)-DNA and hepatitis C virus (HCV)-RNA were assayed in serum by polymerase chain reaction (PCR). Serum hepatitis G virus (HGV)-RNA was determined by PCR in 74 patients. RESULTS: Of 1075 patients studied, the cause of the increased serum ALT levels remained elusive after appropriate testing in 109 patients (10.1%). Liver biopsies from these patients showed non-specific changes in 32.7% of cases, non-alcoholic steatohepatitis (NASH) in 15.8%, and chronic hepatitis or cirrhosis in 51.5%. HBV-DNA and/or HCV-RNA was detected more frequently in cryptogenic liver disease than in healthy blood donors (26.7% v 3.4%; p<0.001). HGV-RNA was found in only one patient. The proportion of cases with detectable HBV-DNA or HCV-RNA was 14.3% in patients with non-specific changes or NASH, 30.7% in patients with chronic hepatitis, and 61.5% in patients with cirrhosis. Cirrhosis was found more frequently in patients with positive HBV-DNA and/or HCV-RNA in serum than in those who tested negatively (p=0.005). CONCLUSIONS: In our series, patients in whom biochemical and serological data did not determine the aetiology of the disease represented 10% of all cases referred for liver biopsy for persistent elevation of serum transaminases. Approximately 50% of patients had chronic hepatitis or cirrhosis and the remainder had NASH or non-specific changes. Occult viral infections were found in a high proportion of cases in the first group and in a low percentage of patients in the second.

Rodríguez-López M, Riezu-Boj JI, Ruiz M, Berasain C, Civeira MP, Prieto J, Borrás-Cuesta F. · Universidad de Navarra, Facultad de Medicina, Departamento de Medicina Interna, Pamplona, Spain. · J Gen Virol. · Pubmed #10092013 links to  free full text

Abstract: The immunogenicity of variable regions of hepatitis C virus (HCV) proteins was studied by ELISA by using 543 synthetic peptides from 120 variable regions and 90 sera from HCV-infected patients. Some regions from certain genotypes were less immunogenic, or even non-immunogenic, compared with their equivalents in other genotypes. However, the mean recognition of all peptides from genotypes 1a, 1b and 3 by sera infected with genotypes 1a, 1b and 3, respectively, showed no significant differences, suggesting a similar overall immunogenicity of variable regions from these genotypes. Proteins NS4a, NS4b and NS5a were found to be the most immunogenic. Recognition of individual peptides by the sera of infected patients showed that the humoral response against HCV is patient-dependent. The work shows that 15-mer peptides may encompass several B-cell epitopes. These epitopes may lie in slightly different positions in different genotypes. Thirty-one percent of the 543 peptides were recognized by some of the 35 healthy donors. This may be a reflection of the large number of antigens to which they had been exposed, but it may also reflect a strategy of HCV to respond to immune pressure. After selection and modification, a set of 40 peptides was used to assess genotypes 1a, 1b, 1, 2 and 3 in the sera of HCV-infected patients, with sensitivities of 34.1, 48.5, 68.8, 58.3 and 48.9% and specificities of 100, 99.1, 97.1, 99.5 and 99%, respectively. The overall sensitivity and specificity for the assessment of genotypes 1, 2 and 3 were 64 and 98%, respectively.